This invention provides new synthetic routes to 5,5'-unsubstituted-meso-halocarbyl dipyrromethanes which are useful precursors to linear di-, tri-, tetra-and polypyrrolic compounds, as well as cyclic polypyrrolic compounds such as porphyrins, azaporphyrins, expanded polypyrrolic macrocycles and their metal derivatives.
Cyclic polypyrrolic compounds such as porphyrins, azaporphyrins and expanded polypyrrolic compounds have found many uses both as their non-metallated free-base form as well as their metallated forms. Porphyrins in their non-metallated form have been used as photosensitizers in the novel form of cancer treatment known as photodynamic therapy PDT ("Photodynamic Therapy: Basic Principles and Clinical Applications"; B. Henderson and T. J. Dougherty, Eds., Marcel Dekker, New York, 1992) while in their metallated form (particularly as Fe, Co, Mn, and Cr) have been used as catalysts for air oxidations of hydrocarbons (Ellis and Lyons, Catalysis Lett., 3, 389 1989; Lyons and Ellis, Catalysis Lett., 8, 45 1991; U.S. Pat. Nos. 4,900,871; 4,970,348) as well as degradation of lignin in the pulp and paper industry (U.S. Pat. Nos. 4,892,941; 5,077,394). Azaporphyrins (U.S. Pat. No. 5,124,449) and expanded polypyrrolic macrocycles (B. Ehrenberg, A. Lavi, Y. Nitzan, Z. Malik, H. Ladan, F. M. Johnson and J. L. Sessler, Proc. SPIE-Int. Soc. Opt. Eng. 1645 259, 1992; B. Franck, G. Fuelling, M. Gosmann, G. Knuebel, H. Mertes and D. Schroeder, Proc. SPIE-Int. Soc. Opt. Eng. 997 107 1989) have also found their use in PDT. In particular, the latter group of compounds, due to their ability to coordinate with larger paramagnetic metal ions such as Gd and Tc (due to the larger central cavity), have been examined as potential radiopharmaceuticals and paramagnetic contrast agents in magnetic resonance imaging MRI (J. L. Sessler, T. Murai, G. Hemmi, Inorg. Chem., 28, 3390 1989). Variation of the type and position of the peripheral substituents of these macrocycles is known to change their photophysical, photochemical and electrochemical properties which in turn alter their activity.
Catalytic activity of porphyrins is known to increase with the introduction of electron-withdrawing substituents at all peripheral positions, beta as well as meso. Although some useful substituents can be introduced onto the macrocycle after its formation e.g. halogens; F, Cl or Br (U.S. Pat. Nos. 4,892,941; 4,970,348), nitro NO.sub.2 (U.S. Pat. No. 5,120,882) and cyano CN (U.S. Pat. No. 5,118,886), certain groups e.g. hydrohalocarbyl, halocarbyl (Lindsey and Wagner, J. Org. Chem., 54 828 1989) have to be introduced at the appropriate position of the precursor fragments during cyclization. Therefore if a porphyrin is to be modified to produce an efficient oxidation catalyst, it is preferable to have unsubstituted peripheral positions or have appropriate carbon bonded substituents (e.g. perhaloalkyl, perhaloaryl etc.) already in place.
Dipyrromethanes (1; see J. B. Paine in "The Porphyrins", D. Dolphin, Ed., Academic Press, New York, Vol. I, pages 101 and 163-234, 1978) are the most commonly used precursors for porphyrins. In addition, they are used to prepare tripyrrins and a,c-biladienes in the stepwise build-up of unsymmetrically substituted porphyrins, azaporphyrins and expanded polypyrrolic macrocycles. The use of dipyrromethanes for the synthesis of porphyrins containing electron-withdrawing groups in all peripheral positions has been limited by the inaccessibility of 5,5'-unsubstituted dipyrromethanes (1; R.sup.1 =R.sup.7 =H) in which beta (R.sup.2, R.sup.3, R.sup.5, R.sup.6) and meso groups (R.sup.4) are electron-withdrawing. ##STR1##
Dipyrromethanes carrying electron-withdrawing beta substituents are synthetically less useful since the presence of such groups renders the dipyrromethane highly unreactive at the 5,5' positions. However, if the beta positions are unsubstituted (R2=R3=R5=R6=H) and the meso position carries an electron-withdrawing substituent (e.g. R4=halohydrocarbyl or halocarbyl), the macrocycle derived from it will carry electron-withdrawing groups at the bridging carbons and will also have the beta positions available for subsequent functionalization with electron-withdrawing substituents (e.g. halogens).
Treibs and Jacob, "Benzoylierung in der Pyrrol-Reihe, II", Liebigs Ann Chem, 733 27 1970 disclose reaction of benzoyl chloride with alkylpyrroles to give dibenzoyl-.alpha.-methylene pyrrolines, with some .beta.-acetylpyrroles to give benzoates of their enol forms and with .alpha.-carboxypyrroles to form mixed anhydrides.
Allen, Kwong-Chip, Lin, Nguyen and Tidwell, "Formation and reactivity of 1-pyrrolyl-2,2,2-trifluoroethyl cations", Canad. J. Chem., 68, 1709 1990 disclose that reaction of 1-methylpyrrole with trifluoroacetic anhydride gives 1-methyl-2-trifluoroacetyl-pyrrole, which is then reduced to the alcohol, which is then in turn converted to the p-nitrobenzoate.
Wijesekera and Wagner, "Synthetic Route to meso-Tetrahydrocarbyl or Substituted Hydrocarbyl Porphyrins and Derivatives", U.S. Pat. No. 5,241,062 disclose that reaction of pyrrole with trifluoroacetic anhydride gives 2-trifluoroacetylpyrrole, which is then reduced to the corresponding alcohol.